Triazepinones, process for their preparation and their therapeutic application

ABSTRACT

Described are compound of the formula (I) defined herein which are useful, for example, in the treatment of diabetes. Also described is a method for preparing the compounds.

The present invention relates to novel triazepine derivatives, to aprocess for their preparation and to pharmaceutical compositionscontaining them.

The invention relates more specifically to novel triazepine derivativeswhich are useful in therapy for inhibiting the reaction of glucose or ofits oxidation products (α-dicarbonyl derivatives such as glyoxal ormethylglyoxal) with the amine groups of proteins, and which consequentlyfind an application in the treatment of diabetes and its complications.

The subject of the present invention is thus compounds of generalformula:

in which:

R is chosen from a hydrogen atom, a methyl group and a group of formula:

 and

R₁, R₂, R₃ and R₄ are chosen, independently of each other, from:

a) a hydrogen atom,

b) a C₁-C₈ alkyl, cyclo(C₃-C₈)alkyl, cyclo(C₃-C₈)alkyl(C₁-C₈)alkyl,cyclo(C₃-C₈)alkyloxy(C₁-C₈)alkyl,cyclo(C₃-C₈)alkyl(C₁-C₈)alkoxy(C₁-C₈)alkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,(C₁-C₈) hydroxyalkyl, (C₆-C₁₄) aryl, (C₆-C₁₄) heteroaryl,hetero(C₆-C₁₄)aryl(C₁-C₈)alkyl, (C₆-C₁₄)aryl(C₁-C₈)alkyl,(C₆-C₁₄)aryl(C₁-C₈)alkyl(C₆-C₁₄)aryl, (C₆-C₁₄)aryloxy(C₁-C₈)alkyl or(C₆-C₁₄)aryl (C₁-C₈)alkyloxy(C₁-C₈)alkyl group,

it being possible for the various aryl, cycloalkyl and heteroaryl groupsto be substituted themselves with 1 to 3 substituents chosen from a(C₁-C₈) alkyl group, a C₁-C₈ alkoxy group, a halogen chosen fromfluorine, chlorine, bromine and iodine, and a trifluoromethoxy,hydroxyl, cyano, nitro, amino, carbamoyl, C₁-C₈ alkylamino, (C₁-C₈)alkylthio(C₁-C₈)alkylsulphinyl, C₁-C₈ alkylsulphonyl, sulphonylamino orsulphamoyl (C₁-C₈)alkylcarbonylamino group, it being possible for two ofthese groups to form a methylenedioxy group;

it being possible for R₁ and R₂ as well as R₃ and R₄ to form, with thenitrogen which bears them, a group of general formula:

in which n represents a number from 1 to 4 and X is chosen from —CH₂—,—O—, —S—, —NH— and —NR′—, R′having the meaning given for R₁ in b);

c) a group of formula:

in which Q represents a linear or branched C₂-C₁₄ alkylene group;

R₅ and R₆ are chosen, independently of each other, from a hydrogen atomand a group mentioned above in b);

it being possible for R₅ and R₆ also to form, with the nitrogen whichbears them, a group of general formula (1);

d) a bicyclic amine residue of fused or bridged type, and their saltswith pharmaceutically acceptable acids.

The C₁-C₈ alkyl groups can be linear or branched. As examples, mentionmay be made of methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl andpentyl groups.

The C₁-C₈ alkoxy groups can similarly be linear or branched. Asexamples, mention may be made of methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy and pentoxy groups.

The term aryl group is understood to refer to a monocyclic, bicyclic ortricyclic group containing from 6 to 14 carbon atoms. As examples of anaryl group mention may be made of phenyl, α-naphthyl, β-naphthyl andfluorenyl groups.

The heteroaryl groups can be chosen in particular from pyridyl,pyrimidyl, pyrrolyl, furyl, thienyl, quinolyl, indolyl, benzothienyl,benzofuryl, benzopyranyl, benzothiopyranyl, dibenzofuryl, carbazolyl andbenzothiazinyl groups.

The expression bicyclic amine residue of fused or bridged type isunderstood to denote residues of the type:

The compounds of general formula (I) contain basic nitrogen atoms andcan be salified with inorganic or organic acids. Examples of salts, withacids, of the compounds of general formula (I) include pharmaceuticallyacceptable salts such as, in a non-exhaustive manner, hydrochloride,hydrobromide, sulphate, succinate, maleate, fumarate, malate, tartrateand sulphonates such as methanesulphonate, benzenesulphonate andtoluenesulphonate.

The compounds of formula I can be prepared by reaction of α-ketoaldehydes of general formula:

with biguanides of general formula:

Biguanides of formula (III) are described in particular in U.S. Pat. No.2,455,896, FR-A-2,085,665, FR-A-1,518,398, FR-A-2,230,347 and U.S. Pat.No. 2,961,377.

This reaction can be carried out in an alcohol of low molecular weight(for example methanol) or, more advantageously, in water.

The structure of the compounds obtained was confirmed by analysis of the¹H, ¹⁵N and ¹³C spectra.

The example which follows illustrates the preparation of the compoundsof formula (I).

EXAMPLE 1 Preparation of2-amino-4-dimethylamino-7-methyl-5,7-dihydro(1,3,5)triazepin-6-one (andhydrochloride)

25.8 g (0.2 mol) of base N,N-dimethylbiguanide (metformine) and 100 mlof water are introduced into a 250 ml three-necked flask; after completedissolution, the solution is cooled and, while maintaining the internaltemperature between 0 and +5°, 34 ml (0.210 mol) of aqueous 40%methylglyoxal (pyruvaldehyde) solution are run in.

The mixture is stirred for 1 hour at +5° C. A crystalline precipitateforms. The mixture is stirred for a further 4 hours at +20° C. Theproduct is filtered off on a sinter funnel, washed with water and driedunder vacuum. A pale cream-white product weighing 18.2 g (yield: 50%)and melting at 264‥266° C. (Köfler bank) is obtained. It isrecrystallized from dimethylformamide. Its hydrochloride was prepared,and this melts at 260-262° C. (Köfler bank).

The compounds of the invention can be used in the treatment of diabetesand its complications.

The chronic complications of diabetes are due to the formation ofAdvanced Glycosylation End-Products, known as AGE's, derived from theglycoxidation reaction between glucose, its oxidation derivatives andthe amino functions of proteins, including the so-called Maillardreactions of glycation of glyoxal, for example.

Compounds of biguanide type, such as metformine, inhibit these reactionsby interfering in the reactions between the amino groups of proteins andthe α-dicarbonyl derivatives of glucose, in particular methylglyoxal.

Now, the theory of glyoxidation in the pathogenesis of diabetescomplications involves several metabolic routes:

It is thus seen that 50% of the AGE products in the body, which areresponsible for the chronic complications of diabetes, are derived fromreactions involving glyoxal.

The value of the compounds of formula (I) is that they are capable ofinhibiting the so-called Maillard reactions by means of a “scavenging”effect on α-dicarbonyl derivatives such as glyoxal, and these compoundstherefore have an antiglycation effect.

This effect of inhibiting the Maillard reaction by the compoundsaccording to the invention has been studied in vitro by assaying theketamines (“fructosamine”) produced during the incubation of albuminwith methylglyoxal in the presence or absence of a compound according tothe invention.

A bovine albumin solution at 6.6 mg/ml in 0.2M pH 7.4 phosphate bufferis incubated with 1 mM methylglyoxal in the presence or absence of2-amino-4-dimethylamino-7-methyl-5,7-dihydro(1,3,5)triazepin-6-one at aconcentration of 1 mM. The incubation is carried out under sterileconditions, at 37° C. for 6 days. At the end of the incubation period,the amount of ketamines formed is measured with a commercially availablefructosamine assay kit, the “FRA” kit, which has the product reference:0757055, Produits Roche S. A.) according to the manufacturer'sinstructions. Under these experimental conditions, the level offructosamine after incubation of the albumin with methylglyoxal in thepresence of2-amino-4-dimethylamino-7-methyl-5,7-dihydro(1,3,5)triazepin-6-one is31% less than that observed when the albumin is incubated withmethylglyoxal in the absence of this triazepinone.

The subject of the present invention is thus pharmaceutical compositionscomprising, as active principle, a compound according to the invention.

The pharmaceutical compositions according to the invention can beprovided in forms intended for parenteral, oral, rectal, permucous orpercutaneous administration.

They will thus be provided in the form of solutions or suspensions forinjection or multi-dose bottles, in the form of plain or coated tablets,sugar-coated tablets, wafer capsules, gelatin capsules, pills, cachets,powders, suppositories or rectal capsules, or solutions or suspensions,for percutaneous use in a polar solvent, or for permucous use.

The excipients which are suitable for such administrations arederivatives of cellulose or microcrystalline cellulose, alkaline-earthmetal carbonates, magnesium phosphate, starches, modified starches andlactose for the solid forms.

For rectal use, cocoa butter or polyethylene glycol stearates are thepreferred excipients.

For parenteral use, water, aqueous solutions, physiological saline andisotonic solutions are the vehicles used most conveniently.

The dosage can vary within a wide range depending on the therapeuticindication and the route of administration, as well as the age and theweight of the individual.

What is claimed is:
 1. A compound of the formula (I):

in which: R is a hydrogen atom, a methyl group or a group of theformula:

 and R₁, R₂, R₃ and R₄ are, independently of each other: a) a hydrogenatom, or b) a C₁-C₈ alkyl, cyclo(C₃-C₈)alkyl, orcyclo(C₃-C₈)alkyl(C₁-C₈)alkyl group, the cycloalkyl groups optionallybeing substituted with 1 to 3 substituents chosen from a (C₁-C₈) alkylgroup, a C₁-C₈ alkoxy group, a halogen chosen from fluorine, chlorine,bromine and iodine, and a trifluoromethoxy, hydroxyl, cyano, nitro,amino, carbamoyl, (C₁-C₈) alkyl, C₁-C₈ alkylamino, (C₁-C₈)alkylthio(C₁-C₈)alkylsulphinyl, C₁-C₈ alkylsulphonyl, sulphonylamino orsulphamoyl (C₁-C₈) alkylcarbonylamino group, or a salt thereof with apharmaceutically acceptable acid.
 2. Compound according to claim 1,which is 2-amino-4-dimethylamino-7-methyl-5,7-dihydro(1,3,5)triazepin-6-one, or its salt with a pharmaceutically acceptableacid.
 3. A process for preparing a compound according to claim 1, inwhich a compound of formula:

is reacted with a biguanide of formula:

R, R₁, R₂, R₃, and R₄ having the meaning given in claim
 1. 4. Apharmaceutical composition comprising, as active principle, an effectiveamount of a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 5. A pharmaceutical composition comprising, asactive principle, an effective amount of a compound according to claim 2and a pharmaceutically acceptable carrier.